Problem statement: Uterine myomas are the most common benign tumour of the female genital tract. Myomectomy remains the ‘gold-standard’ treatment for women wishing to preserve their uterus and fertility. However, bleeding is often a problem in myomectomy, and can result in intra-operative hypovolaemic shock, postoperative anaemia and delayed recovery.

Rationale:

Intraoperative local injection of vasopressin causing vasospasm is used most often during myomectomy. However, some serious side effects have also been reported following the use of vasopressin. Hence, we would like to test an alternative drug with equal safety and efficacy profile but fewer adverse effects which can be used in clinical practice.

Novelty: Till date, no study regarding the use of phenylepinephrine in myomectomy have been undertaken. Furthermore, a comparative study of phenylepinephrine and vasopressin as a haemostatic agent during myomectomy has never been conducted.

Expected outcome and application: Phenylephrine if found to be safe and effective can be used as an alternative to vasopressin with similar cost and lesser adverse effects.

^Aim: To compare the effectiveness and safety of vasopressin with phenylepinephrine for reducing blood loss during laparoscopic myomectomy.

Review of literature

A double-blind randomized study was conducted by R Soliman et al (2020) on 194 patients classified into two groups (vasopressin group and control group) to evaluate the effect of intramyometrial vasopressin on blood loss and the associated cardiovascular complications during myomectomy. They found that the heart rate decreased significantly in both groups, but the decrease was lower with vasopressin than the control group (P < 0.05). The mean arterial blood pressure increased significantly in both groups, but the increase was higher with vasopressin than the control group (P < 0.05). The amount of blood loss decreased significantly with vasopressin than the control groups (P = 0.001). The number of transfused packed red blood cells was lower with vasopressin than the control group (P = 0.001). The incidence of hypertension, bradycardia and atrial extrasystole was higher with vasopressin than the control group (P = 0.005, P = 0.012, P = 0.033, respectively).

Methodology

Study design: Randomised controlled trial

Study participants:

Inclusion criteria:

1.     Age between 15-49 years.

2.     BMI between 18-29.9.

3.     1-5 symptomatic intramural myomas

4.     Presenting with abnormal uterine bleeding, pelvic pressure or pain, infertility or recurrent miscarriage and are candidates for abdominal myomectomy.

5.     Largest uterine fibroid size of <10 cm

6.     not pregnant at the time of presentation (i.e. negative urine pregnancy test or last menstrual period within the last 4 weeks);

7.     appropriate medical status for laparoscopic surgery (American Society of Anesthesiologists Physical Status Classification 1 or 2).

Exclusion criteria:

1.        History of previous abdominal or pelvic surgery  except Cesarian section.

2.        History of pelvic or ovarian endometriosis or abdominal tuberculosis.

3.        Patient with subserous or submucosal fibroid or adenomyoma.

4.        Patients who are not candidate for laparoscopic myomectomy.

5.        any pelvic abnormalities requiring concomitant surgery

6.        myoma with a maximal diameter of 10 cm based on pre-operative ultrasound

7.        Allergy to phenylephrine and vasopressin

8.        Hypertension, Diabetes Mellitus, Cardiac and pulmonary diseases. (ASA>2)

9.        Obesity BMI > 30 kg/m².

10.   Anemia Hb < 10 g/dL.

11.   Bleeding disorder or use of anticoagulation.

12.   Preoperative use of hormonal therapy as GnRH analogues or oral contraceptive pills or mifepristone or ulipristal acetate within 3 months preceding surgery.

13.   more than five myomas

14.   conversion to open surgery

15.   need for adhesiolysis

16.   Pregnancy.

17.   Postmenopausal.

18.   Not giving written informed consent.

Sampling population : reproductive age group females between 15 and 49 years

Sample size : Assuming a true difference in means between the test and the reference group of 0 units, a pooled standard deviation of 23.17 units (from previous study), the study would require a sample size of: 67 for each group (i.e. a total sample size of 134, assuming equal group sizes), to achieve a power of 80% and a level of significance of 5%, for declaring that the test drug is not inferior to the active control drug at 10 units margin of non-inferiority (assuming that a smaller mean is desirable).

 In other words, if we select a random sample of 67 from each population, and determine that the difference in the two means is 0 units, and the pooled standard deviation is 23.17 units, we would have 80% power to declare that the mean of the test drug group is at the most 10 units higher than the mean of the active control drug group (assuming that a smaller mean is desirable).

Reference: Dhand, N. K., & Khatkar, M. S. (2014). Statulator: An online statistical calculator. Sample Size Calculator for Comparing Two Independent Means. Accessed 23 December 2022 at http://statulator.com/SampleSize/ss2M.html

Study procedure: This will be a prospective randomised controlled trial to be conducted at Department of Obstetrics and Gynaecology, AIIMS, Patna after ethical approval. Total of women fulfilling the inclusion criteria will be included in the study and their demographic details will be collected

   Women with symptomatic myomas will be screened for this study. All participants will undergo transvaginal and/or transabdominal ultrasonography or MRI (within 30 days preceding surgery), in which the number, size and location of myomas will be assessed and recorded. Informed written consent of patients and their relatives will be taken. They will be assigned to either vasopressin or phenylepinephrine group in a 1:1 ratio using a random permuted-block algorithm via an interactive Web-based response system. The study coordinator, who will not be involved in the randomization procedure, will prepare all sequentially numbered, opaque, sealed envelopes containing the assigned intervention to ensure that the sequence will be concealed. The surgeon will be blinded to group allocation. A single surgeon will perform all laparoscopic myomectomies using a 10-mm umbilical trocar and three ancillary 5-mm trocars. To reduce blood loss, only the haemostatic agent (either phenylepinephrine or vasopressin) assigned will be injected into the serosal and/or myometrium overlying the myoma before the uterine incision. In the phenylepinephrine group, dilute phenylepinephrine {0.5 mg of epinephrine) in 50 ml of saline solution will be used, taking care to use no more than 200 ml of solution per subject. In the vasopressin group, dilute vasopressin (5 units in 50 ml of saline solution) will be used, taking care to inject no more than 200 ml of solution per subject. During injection, careful electrocardiographic monitoring will be used to detect arrhythmias. Systolic and diastolic blood pressure and heart rate will be measured accurately, and an electrocardiogram will be performed in each subject 5 min before and after the injection of phenylepinephrine or vasopressin. Total operative time will be defined as the time from skin incision to skin closure. The times required to perform each phase will be measured and calculated with a digital time counter: entry time (defined as the time from the start of skin incision until the start of epinephrine or vasopressin administration); enucleation time of all myomas; suturing time of all uterine wall defects; morcellation time; haemostasis time (defined as the time from removal of the morcellator until confirmation of haemostasis and washing of the pelvic cavity); and skin closure time. The volume of operative blood loss will be calculated by adding the blood aspirated and irrigation fluid used minus the volume of irrigation fluid used. At the end of each surgical procedure, the degree of total surgical difficulty, enucleation difficulty and suturing difficulty will be evaluated by the surgeon using a 5-point Likert scale (Very difficult – Difficult – Neutral – Easy – Very easy) varying from 1 (very low difficulty) to 5 (very high difficulty). Postoperative pain assessments will be performed using a Visual analogue scale at 12, 24 and 48 h after surgery by several independent assessors. The scale will be presented as a 10-cm line with verbal descriptors ranging from ‘no pain’ to ‘pain as bad as it could be’. In both study groups, blood samples will be taken within 24 h after surgery, and change in haemoglobin and hematocrit level will be defined as the difference between pre-operative values and values on the first postoperative day. The subjects will be discharged from the hospital after bowel activity restoration, ambulation, lack of postoperative fever and no need for narcotic analgesics. Length of hospital stay will be defined as the number of days from surgery to discharge. All intra- and postoperative complications arising within 30 days of surgery will be recorded. All subjects will be seen for follow-up assessments 1 week and 1 month after surgery

Outcome variables:

Primary outcomes:

Intraoperative blood loss estimated by calculating the sum of canisters containing irrigation fluids and suctioned (ml)blood minus used irrigation solution

Secondary outcomes:

1.        Preoperative and postoperative haemoglobin and haematocrit values- 24 hours before and 24 hours after

2.     Perioperative blood pressure and HR -up to first four hours postoperative.

3.        Blanching time

4.        Mean drug concentration required for blanching

5.        Operation time -measured from incision of first myoma to serosal closure of last myoma wound in minutes

6. Anaesthesia time

7. Subjective surgical difficulty using 5-point Likert scale

8. Post-operative pain score

9. Time of ambulation [ Time Frame: within 12 hours postoperative ]

interval the operation ended up patient’s walking with assistance in hours

10. Post-operative hospital stay [ Time Frame: within 3 days postoperative ]

Days

11.   Rate of complications and adverse effects to the drug- conversion to open surgery, intra-operative and post-operative complications, bradycardia, arrhythmias between the two groups.

Statistical analysis: Data collected will be compiled, tabulated and analysed using SPSS .

Appropriate tests of significance will be applied and p value<0.05 will be considered significant.